. This proposal addresses the possible role of TNF-alpha and nitric oxide in tuberculosis reactivation. Efforts will be directed toward evaluating the significance of INF-gamma, TNF- alpha and macrophage nitric oxide synthase (iNOS), which play critical roles in host defence, in the latent and reactivation phase of infection. These will be studied in a murine model with disruption of the TNF receptor gene. Results will be analyzed by several parameters, such as histopathologic examination, immunohistochemical studies to define iNOS expression and cellular components of granulomas and reverse transcription and PCR to evaluate cytokine expression. These would be correlated with tissue bacterial load and disease progression. It is expected that these studies will yield information that could afford a better understanding of the natural history of tuberculosis and ultimately lead to the development of better therapeutic and preventive strategies.